Polypharmacology: Challenges and opportunities in drug discovery

Journal of Medicinal Chemistry

Volumn 57, Issue 19, 2014, Pages 7874-7887

  Anighoro, Andrew ^a   Bajorath, Jürgen ^b   Rastelli, Giulio ^a  

^a UNIVERSITY OF MODENA AND REGGIO EMILIA   (Italy)

^b UNIVERSITY OF BONN   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

AGENTS ACTING ON THE PERIPHERAL NERVOUS AND NEUROMUSCULAR SYSTEMS; ANTINEOPLASTIC AGENT; BORTEZOMIB; CDBT; CLOZAPINE; LADOSTIGIL; LEUCETTINE L41; MDG 892; MEBENDAZOLE; METHOTREXATE; NELFINAVIR; PRENYLAMINE; PROTEIN FARNESYLTRANSFERASE INHIBITOR; PUH 71; SILDENAFIL; SULFADOXINE; SUNITINIB; THALIDOMIDE; TRASTUZUMAB; UNCLASSIFIED DRUG; ZOLMITRIPTAN;

CANCER THERAPY; CENTRAL NERVOUS SYSTEM DISEASE; COMBINATION CHEMOTHERAPY; DRUG DEVELOPMENT; DRUG POTENCY; DRUG REPOSITIONING; DRUG SELECTIVITY; DRUG STRUCTURE; INTERMETHOD COMPARISON; MOLECULARLY TARGETED THERAPY; NEOPLASM; POLYPHARMACOLOGY; REVIEW; BRAIN DISEASES; DRUG COMBINATION; DRUG DESIGN; HUMAN; NEOPLASMS; STRUCTURE ACTIVITY RELATION;

BRAIN DISEASES; DRUG DESIGN; DRUG REPOSITIONING; DRUG THERAPY, COMBINATION; HUMANS; NEOPLASMS; POLYPHARMACOLOGY; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 84907943686     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm5006463     Document Type: Review

References (92)

1. Hopkins, A. L. Network Pharmacology: The Next Paradigm in Drug Discovery Nat. Chem. Biol. 2008, 4, 682-690
2. Boran, A. D. W.; Iyengar, R. Systems Approaches to Polypharmacology and Drug Discovery Curr. Opin. Drug Discovery Dev. 2010, 13, 297-309
3. Mestres, J.; Gregori-Puigjané, E. Conciliating Binding Efficiency and Polypharmacology Trends Pharmacol. Sci. 2009, 30, 470-474
4. Peters, J.-U. Polypharmacology-Foe or Friend? J. Med. Chem. 2013, 56, 8955-8971
5. Hu, Y.; Bajorath, J. Compound Promiscuity: What Can We Learn from Current Data? Drug Discovery Today 2013, 18, 644-650
6. http://www.scopus.com (accessed Dec 2013).
7. Jalencas, X.; Mestres, J. On the Origins of Drug Polypharmacology Med. Chem. Commun. 2012, 4, 80-87
8. Lu, J.-J.; Pan, W.; Hu, Y.-J.; Wang, Y.-T. Multi-Target Drugs: The Trend of Drug Research and Development PLoS One 2012, 7, e40262
9. Adams, J. C.; Keiser, M. J.; Basuino, L.; Chambers, H. F.; Lee, D.-S.; Wiest, O. G.; Babbitt, P. C. A Mapping of Drug Space from the Viewpoint of Small Molecule Metabolism PLoS Comput. Biol. 2009, 5, e1000474
10. Tian, L.; Zhang, S. Mapping Drug-Target Interaction Networks. Proceedings of the Annual International Conference of the IEEE Engineering in Medicine and Biology Society, 2009; EMBC: Piscataway, NJ, 2009; pp 2336-2339.
11. Simon, Z.; Peragovics, á.; Vigh-Smeller, M.; Csukly, G.; Tombor, L.; Yang, Z.; Zahoránszky-Köhalmi, G.; Végner, L.; Jelinek, B.; Hári, P.; Hetényi, C.; Bitter, I.; Czobor, P.; Málnási-Csizmadia, A. Drug Effect Prediction by Polypharmacology-Based Interaction Profiling J. Chem. Inf. Model. 2012, 52, 134-145
12. Yildirim, M. A.; Goh, K.-I.; Cusick, M. E.; Barabási, A.-L.; Vidal, M. Drug-Target Network Nat. Biotechnol. 2007, 25, 1119-1126
13. Reddy, A. S.; Zhang, S. Polypharmacology: Drug Discovery for the Future Expert Rev. Clin. Pharmacol. 2013, 6, 41-47
14. Rask-Andersen, M.; Almén, M. S.; Schiöth, H. B. Trends in the Exploitation of Novel Drug Targets Nat. Rev. Drug Discovery 2011, 10, 579-590
15. Hu, Y.; Bajorath, J. Polypharmacology Directed Compound Data Mining: Identification of Promiscuous Chemotypes with Different Activity Profiles and Comparison to Approved Drugs J. Chem. Inf. Model. 2010, 50, 2112-2118
16. Hu, Y.; Bajorath, J. High-Resolution View of Compound Promiscuity F1000Research 2013, 2, 144
17. Altieri, D. C. Mitochondrial Hsp90 Chaperones as Novel Molecular Targets in Prostate Cancer Future Oncol. 2010, 6, 487-489
18. Wright, J. J. Combination Therapy of Bortezomib with Novel Targeted Agents: An Emerging Treatment Strategy Clin. Cancer Res. 2010, 16, 4094-4104
19. Sgobba, M.; Rastelli, G. Structure-Based and in Silico Design of Hsp90 Inhibitors ChemMedChem 2009, 4, 1399-1409
20. Lu, X.; Xiao, L.; Wang, L.; Ruden, D. M. Hsp90 Inhibitors and Drug Resistance in Cancer: The Potential Benefits of Combination Therapies of Hsp90 Inhibitors and Other Anti-Cancer Drugs Biochem. Pharmacol. 2012, 83, 995-1004
21. Modi, S.; Stopeck, A.; Linden, H.; Solit, D.; Chandarlapaty, S.; Rosen, N.; DAndrea, G.; Dickler, M.; Moynahan, M. E.; Sugarman, S.; Ma, W.; Patil, S.; Norton, L.; Hannah, A. L.; Hudis, C. HSP90 Inhibition Is Effective in Breast Cancer: A Phase II Trial of Tanespimycin (17-AAG) Plus Trastuzumab in Patients with HER2-Positive Metastatic Breast Cancer Progressing on Trastuzumab Clin. Cancer Res. 2011, 17, 5132-5139
22. Eastman, R. T.; Fidock, D. A. Artemisinin-Based Combination Therapies: A Vital Tool in Efforts to Eliminate Malaria Nat. Rev. Microbiol. 2009, 7, 864-874
23. Conway, D.; Cohen, J. A. Combination Therapy in Multiple Sclerosis Lancet Neurol. 2010, 9, 299-308
24. CTEP, Cancer Therapy Evaluation Program. http://ctep.cancer.gov (accessed Dec 2013).
25. Gadgeel, S. M.; Ivy, P.; Chen, W.; Mauer, J.; Smith, D.; Lorusso, P. Analysis of Lung Cancer Patients Enrolled in CTEP (Cancer Therapy Evaluation Program)-Sponsored Phase I Trials Clin. Lung Cancer 2011, 12, 218-223
26. Luke, J. J.; Rubinstein, L. V.; Smith, G. L.; Ivy, S. P.; Harris, P. J. Similar Efficacy for Phase I Trials in Comparison with DTIC for Advanced Malignant Melanoma: An Analysis of Melanoma Outcomes in CTEP-Sponsored Phase I Trials 1995-2011 Melanoma Res. 2013, 23, 152-158
27. Giacomini, K. M.; Krauss, R. M.; Roden, D. M.; Eichelbaum, M.; Hayden, M. R.; Nakamura, Y. When Good Drugs Go Bad Nature 2007, 446, 975-977
28. Overall, C. M.; Kleifeld, O. Tumour Microenvironment-Opinion: Validating Matrix Metalloproteinases as Drug Targets and Anti-Targets for Cancer Therapy Nat. Rev. Cancer 2006, 6, 227-239
29. Aggarwal, M.; Kondeti, B.; McKenna, R. Insights towards Sulfonamide Drug Specificity in α-Carbonic Anhydrases Bioorg. Med. Chem. 2013, 21, 1526-1533
30. Peters, J.-U.; Hert, J.; Bissantz, C.; Hillebrecht, A.; Gerebtzoff, G.; Bendels, S.; Tillier, F.; Migeon, J.; Fischer, H.; Guba, W.; Kansy, M. Can We Discover Pharmacological Promiscuity Early in the Drug Discovery Process? Drug Discovery Today 2012, 17, 325-335
31. Kuhn, M.; Al Banchaabouchi, M.; Campillos, M.; Jensen, L. J.; Gross, C.; Gavin, A.-C.; Bork, P. Systematic Identification of Proteins That Elicit Drug Side Effects Mol. Syst. Biol. 2013, 9, 663
32. Lounkine, E.; Keiser, M. J.; Whitebread, S.; Mikhailov, D.; Hamon, J.; Jenkins, J. L.; Lavan, P.; Weber, E.; Doak, A. K.; Côté, S.; Shoichet, B. K.; Urban, L. Large-Scale Prediction and Testing of Drug Activity on Side-Effect Targets Nature 2012, 486, 361-367
33. Bender, A.; Scheiber, J.; Glick, M.; Davies, J. W.; Azzaoui, K.; Hamon, J.; Urban, L.; Whitebread, S.; Jenkins, J. L. Analysis of Pharmacology Data and the Prediction of Adverse Drug Reactions and Off-Target Effects from Chemical Structure ChemMedChem 2007, 2, 861-873
34. Azzaoui, K.; Hamon, J.; Faller, B.; Whitebread, S.; Jacoby, E.; Bender, A.; Jenkins, J. L.; Urban, L. Modeling Promiscuity Based on in Vitro Safety Pharmacology Profiling Data ChemMedChem 2007, 2, 874-880
35. Lamers, J. M.; Cysouw, K. J.; Verdouw, P. D. Slow Calcium Channel Blockers and Calmodulin. Effect of Felodipine, Nifedipine, Prenylamine and Bepridil on Cardiac Sarcolemmal Calcium Pumping ATPase Biochem. Pharmacol. 1985, 34, 3837-3843
36. Chong, C. R.; Sullivan, D. J. New Uses for Old Drugs Nature 2007, 448, 645-646
37. Keiser, M. J.; Setola, V.; Irwin, J. J.; Laggner, C.; Abbas, A. I.; Hufeisen, S. J.; Jensen, N. H.; Kuijer, M. B.; Matos, R. C.; Tran, T. B.; Whaley, R.; Glennon, R. A.; Hert, J.; Thomas, K. L. H.; Edwards, D. D.; Shoichet, B. K.; Roth, B. L. Predicting New Molecular Targets for Known Drugs Nature 2009, 462, 175-181
38. Boolell, M.; Allen, M. J.; Ballard, S. A.; Gepi-Attee, S.; Muirhead, G. J.; Naylor, A. M.; Osterloh, I. H.; Gingell, C. Sildenafil: An Orally Active Type 5 Cyclic GMP-Specific Phosphodiesterase Inhibitor for the Treatment of Penile Erectile Dysfunction Int. J. Impotence Res. 1996, 8, 47-52
39. Silverman, W. A. The Schizophrenic Career of a Monster Drug Pediatrics 2002, 110, 404-406
40. Cronstein, B. N. Low-Dose Methotrexate: A Mainstay in the Treatment of Rheumatoid Arthritis Pharmacol. Rev. 2005, 57, 163-172
41. Nygren, P.; Fryknäs, M.; Agerup, B.; Larsson, R. Repositioning of the Anthelmintic Drug Mebendazole for the Treatment for Colon Cancer J. Cancer Res. Clin. Oncol. 2013, 139, 2133-2140
42. Corbett, A.; Williams, G.; Ballard, C. Drug Repositioning: An Opportunity To Develop Novel Treatments for Alzheimers Disease Pharmaceuticals (Basel, Switz.) 2013, 6, 1304-1321
43. Knight, Z. A.; Lin, H.; Shokat, K. M. Targeting the Cancer Kinome through Polypharmacology Nat. Rev. Cancer 2010, 10, 130-137
44. Zhang, J.; Yang, P. L.; Gray, N. S. Targeting Cancer with Small Molecule Kinase Inhibitors Nat. Rev. Cancer 2009, 9, 28-39
45. Blanc, J.; Geney, R.; Menet, C. Type II Kinase Inhibitors: An Opportunity in Cancer for Rational Design Anti-Cancer Agents Med. Chem. 2013, 13, 731-747
46. Palmieri, L.; Rastelli, G. αC Helix Displacement as a General Approach for Allosteric Modulation of Protein Kinases Drug Discovery Today 2013, 18, 407-414
47. Di Desidero, T.; Fioravanti, A.; Orlandi, P.; Canu, B.; Giannini, R.; Borrelli, N.; Man, S.; Xu, P.; Fontanini, G.; Basolo, F.; Kerbel, R. S.; Francia, G.; Danesi, R.; Bocci, G. Antiproliferative and Proapoptotic Activity of Sunitinib on Endothelial and Anaplastic Thyroid Cancer Cells via Inhibition of Akt and ERK1/2 Phosphorylation and by Down-Regulation of Cyclin-D1 J. Clin. Endocrinol. Metab. 2013, 98, E1465-1473
48. Dar, A. C.; Das, T. K.; Shokat, K. M.; Cagan, R. L. Chemical Genetic Discovery of Targets and Anti-Targets for Cancer Polypharmacology Nature 2012, 486, 80-84
49. Xie, L.; Evangelidis, T.; Xie, L.; Bourne, P. E. Drug Discovery Using Chemical Systems Biology: Weak Inhibition of Multiple Kinases May Contribute to the Anti-Cancer Effect of Nelfinavir PLoS Comput. Biol. 2011, 7, e1002037
50. Hearn, J. M.; Romero-Canelón, I.; Qamar, B.; Liu, Z.; Hands-Portman, I.; Sadler, P. J. Organometallic Iridium(III) Anticancer Complexes with New Mechanisms of Action: NCI-60 Screening, Mitochondrial Targeting, and Apoptosis ACS Chem. Biol. 2013, 8, 1335-1343
51. Laufer, S.; Bajorath, J. New Frontiers in Kinases: Second Generation Inhibitors J. Med. Chem. 2014, 57, 2167-2168
52. Curtin, N. PARP Inhibitors for Anticancer Therapy Biochem. Soc. Trans. 2014, 42, 82-88
53. Ekblad, T.; Camaioni, E.; Schüler, H.; Macchiarulo, A. PARP Inhibitors: Polypharmacology versus Selective Inhibition FEBS J. 2013, 280, 3563-3575
54. Echeverría, P. C.; Bernthaler, A.; Dupuis, P.; Mayer, B.; Picard, D. An Interaction Network Predicted from Public Data as a Discovery Tool: Application to the Hsp90 Molecular Chaperone Machine PLoS One 2011, 6, e26044
55. Moulick, K.; Ahn, J. H.; Zong, H.; Rodina, A.; Cerchietti, L.; Gomes DaGama, E. M.; Caldas-Lopes, E.; Beebe, K.; Perna, F.; Hatzi, K.; Vu, L. P.; Zhao, X.; Zatorska, D.; Taldone, T.; Smith-Jones, P.; Alpaugh, M.; Gross, S. S.; Pillarsetty, N.; Ku, T.; Lewis, J. S.; Larson, S. M.; Levine, R.; Erdjument-Bromage, H.; Guzman, M. L.; Nimer, S. D.; Melnick, A.; Neckers, L.; Chiosis, G. Affinity-Based Proteomics Reveal Cancer-Specific Networks Coordinated by Hsp90 Nat. Chem. Biol. 2011, 7, 818-826
56. Knox, A. J. S.; Price, T.; Pawlak, M.; Golfis, G.; Flood, C. T.; Fayne, D.; Williams, D. C.; Meegan, M. J.; Lloyd, D. G. Integration of Ligand and Structure-Based Virtual Screening for the Identification of the First Dual Targeting Agent for Heat Shock Protein 90 (Hsp90) and Tubulin J. Med. Chem. 2009, 52, 2177-2180
57. Owellen, R. J.; Donigian, D. W.; Hartke, C. A.; Dickerson, R. M.; Kuhar, M. J. The Binding of Vinblastine to Tubulin and to Particulate Fractions of Mammalian Brain Cancer Res. 1974, 34, 3180-3186
58. Zhang, Q.; Zhai, S.; Li, L.; Li, X.; Zhou, H.; Liu, A.; Su, G.; Mu, Q.; Du, Y.; Yan, B. Anti-Tumor Selectivity of a Novel Tubulin and HSP90 Dual-Targeting Inhibitor in Non-Small Cell Lung Cancer Models Biochem. Pharmacol. 2013, 86, 351-360
59. Anighoro, A.; Stumpfe, D.; Heikamp, K.; Bajorath, J.; Rastelli, G. Targeting Hsp90 Interactome Using in Silico Polypharmacology Approaches Chim. Ind. 2013, 4, 105-106
60. Stevens, R. C.; Cherezov, V.; Katritch, V.; Abagyan, R.; Kuhn, P.; Rosen, H.; Wüthrich, K. The GPCR Network: A Large-Scale Collaboration to Determine Human GPCR Structure and Function Nat. Rev. Drug Discovery 2013, 12, 25-34
61. Shoichet, B. K.; Kobilka, B. K. Structure-Based Drug Screening for G-Protein-Coupled Receptors Trends Pharmacol. Sci. 2012, 33, 268-272
62. Roth, B. L.; Sheffler, D. J.; Kroeze, W. K. Magic Shotguns versus Magic Bullets: Selectively Non-Selective Drugs for Mood Disorders and Schizophrenia Nat. Rev. Drug Discovery 2004, 3, 353-359
63. Lipina, T. V.; Palomo, V.; Gil, C.; Martinez, A.; Roder, J. C. Dual Inhibitor of PDE7 and GSK-3-VP1.15 Acts as Antipsychotic and Cognitive Enhancer in C57BL/6J Mice Neuropharmacology 2013, 64, 205-214
64. Lipina, T. V.; Wang, M.; Liu, F.; Roder, J. C. Synergistic Interactions between PDE4B and GSK-3: DISC1 Mutant Mice Neuropharmacology 2012, 62, 1252-1262
65. Youdim, M. B. H.; Buccafusco, J. J. Multi-Functional Drugs for Various CNS Targets in the Treatment of Neurodegenerative Disorders Trends Pharmacol. Sci. 2005, 26, 27-35
66. Bolea, I.; Juárez-Jiménez, J.; de los Ríos, C.; Chioua, M.; Pouplana, R.; Luque, F. J.; Unzeta, M.; Marco-Contelles, J.; Samadi, A. Synthesis, Biological Evaluation, and Molecular Modeling of Donepezil and N -[(5-(Benzyloxy)-1-methyl-1 H -indol-2-yl)methyl]- N -methylprop-2-yn-1-amine Hybrids as New Multipotent Cholinesterase/Monoamine Oxidase Inhibitors for the Treatment of Alzheimers Disease J. Med. Chem. 2011, 54, 8251-8270
67. Tahtouh, T.; Elkins, J. M.; Filippakopoulos, P.; Soundararajan, M.; Burgy, G.; Durieu, E.; Cochet, C.; Schmid, R. S.; Lo, D. C.; Delhommel, F.; Oberholzer, A. E.; Pearl, L. H.; Carreaux, F.; Bazureau, J.-P.; Knapp, S.; Meijer, L. Selectivity, Cocrystal Structures, and Neuroprotective Properties of Leucettines, a Family of Protein Kinase Inhibitors Derived from the Marine Sponge Alkaloid Leucettamine B J. Med. Chem. 2012, 55, 9312-9330
68. León, R.; Garcia, A. G.; Marco-Contelles, J. Recent Advances in the Multitarget-Directed Ligands Approach for the Treatment of Alzheimers Disease Med. Res. Rev. 2013, 33, 139-189
69. Hopkins, A. L.; Mason, J. S.; Overington, J. P. Can. We Rationally Design Promiscuous Drugs? Curr. Opin. Struct. Biol. 2006, 16, 127-136
70. Morphy, J. R.; Harris, C. J. Designing Multi-Target Drugs; Royal Society of Chemistry: Cambridge, U.K., 2012.
71. Bajorath, J.; Peltason, L.; Wawer, M.; Guha, R.; Lajiness, M. S.; Van Drie, J. H. Navigating Structure-Activity Landscapes Drug Discovery Today 2009, 14, 698-705
72. Dimova, D.; Wawer, M.; Wassermann, A. M.; Bajorath, J. Design of Multitarget Activity Landscapes That Capture Hierarchical Activity Cliff Distributions J. Chem. Inf. Model. 2011, 51, 258-266
73. Hu, Y.; Bajorath, J. Promiscuity Profiles of Bioactive Compounds: Potency Range and Difference Distributions and the Relation to Target Numbers and Families Med. Chem. Commun. 2013, 4, 1196-1201
74. Hu, Y.; Bajorath, J. Activity Profile Relationships between Structurally Similar Promiscuous Compounds Eur. J. Med. Chem. 2013, 69, 393-398
75. Morphy, R.; Rankovic, Z. Designed Multiple Ligands. An Emerging Drug Discovery Paradigm J. Med. Chem. 2005, 48, 6523-6543
76. Apsel, B.; Blair, J. A.; Gonzalez, B.; Nazif, T. M.; Feldman, M. E.; Aizenstein, B.; Hoffman, R.; Williams, R. L.; Shokat, K. M.; Knight, Z. A. Targeted Polypharmacology: Discovery of Dual Inhibitors of Tyrosine and Phosphoinositide Kinases Nat. Chem. Biol. 2008, 4, 691-699
77. Besnard, J.; Ruda, G. F.; Setola, V.; Abecassis, K.; Rodriguiz, R. M.; Huang, X.-P.; Norval, S.; Sassano, M. F.; Shin, A. I.; Webster, L. A.; Simeons, F. R. C.; Stojanovski, L.; Prat, A.; Seidah, N. G.; Constam, D. B.; Bickerton, G. R.; Read, K. D.; Wetsel, W. C.; Gilbert, I. H.; Roth, B. L.; Hopkins, A. L. Automated Design of Ligands to Polypharmacological Profiles Nature 2012, 492, 215-220
78. Bottegoni, G.; Favia, A. D.; Recanatini, M.; Cavalli, A. The Role of Fragment-Based and Computational Methods in Polypharmacology Drug Discovery Today 2012, 17, 23-34
79. Gaulton, A.; Bellis, L. J.; Bento, A. P.; Chambers, J.; Davies, M.; Hersey, A.; Light, Y.; McGlinchey, S.; Michalovich, D.; Al-Lazikani, B.; Overington, J. P. ChEMBL: A Large-Scale Bioactivity Database for Drug Discovery Nucleic Acids Res. 2012, 40, D1100-D1107
80. Hu, Y.; Bajorath, J. Systematic Identification of Scaffolds Representing Compounds Active against Individual Targets and Single or Multiple Target Families J. Chem. Inf. Model. 2013, 53, 312-326
81. Keiser, M. J.; Roth, B. L.; Armbruster, B. N.; Ernsberger, P.; Irwin, J. J.; Shoichet, B. K. Relating Protein Pharmacology by Ligand Chemistry Nat. Biotechnol. 2007, 25, 197-206
82. Altschul, S. F. Evaluating the Statistical Significance of Multiple Distinct Local Alignments. In Theoretical and Computational Methods in Genome Research; Suhai, S., Ed.; Springer: New York, 1997; pp 1-14.
83. DeGraw, A. J.; Keiser, M. J.; Ochocki, J. D.; Shoichet, B. K.; Distefano, M. D. Prediction and Evaluation of Protein Farnesyltransferase Inhibition by Commercial Drugs J. Med. Chem. 2010, 53, 2464-2471
84. Carlsson, J.; Yoo, L.; Gao, Z.-G.; Irwin, J. J.; Shoichet, B. K.; Jacobson, K. A. Structure-Based Discovery of A2A Adenosine Receptor Ligands J. Med. Chem. 2010, 53, 3748-3755
85. Hert, J.; Keiser, M. J.; Irwin, J. J.; Oprea, T. I.; Shoichet, B. K. Quantifying the Relationships among Drug Classes J. Chem. Inf. Model. 2008, 48, 755-765
86. Reker, D.; Rodrigues, T.; Schneider, P.; Schneider, G. Identifying the Macromolecular Targets of de Novo-Designed Chemical Entities through Self-Organizing Map Consensus Proc. Natl. Acad. Sci. U.S.A. 2014, 111, 4067-4072
87. Kohonen, T. Self-Organizing Maps; Springer: New York, 2001.
88. Anighoro, A.; Rastelli, G. Enrichment Factor Analyses on G-Protein Coupled Receptors with Known Crystal Structure J. Chem. Inf. Model. 2013, 53, 739-743
89. Selvam, B.; Porter, S. L.; Tikhonova, I. G. Addressing Selective Polypharmacology of Antipsychotic Drugs Targeting the Bioaminergic Receptors through Receptor Dynamic Conformational Ensembles J. Chem. Inf. Model. 2013, 53, 1761-1774
90. Ripphausen, P.; Nisius, B.; Peltason, L.; Bajorath, J. Quo Vadis, Virtual Screening? A Comprehensive Survey of Prospective Applications J. Med. Chem. 2010, 53, 8461-8467
91. Rastelli, G. Emerging Topics in Structure-Based Virtual Screening Pharm. Res. 2013, 30, 1458-1463
92. Rastelli, G.; Degliesposti, G.; Del Rio, A.; Sgobba, M. Binding Estimation after Refinement, a New Automated Procedure for the Refinement and Rescoring of Docked Ligands in Virtual Screening Chem. Biol. Drug Des. 2009, 73, 283-286